Targeted delivery of drugs encapsulated within nanocarriers can potentially ameliorate a number of problems exhibited by conventional ‘free’ drugs, including poor solubility, limited stability, rapid clearing, and, in particular, lack of selectivity, which results in non-specific toxicity to normal cells and prevents the dose escalation necessary to eradicate diseased cells. Passive targeting schemes, which rely on the enhanced permeability of the tumor vasculature and decreased draining efficacy of tumor lymphatics to direct accumulation of nanocarriers at tumor sites (the so-called enhanced permeability and retention, or EPR effect), overcome many of these problems, but the lack of cell-specific interactions needed to induce nanocarrier internalization decreases therapeutic efficacy and can result in drug expulsion and induction of multiple drug resistance (MDR). Furthermore, not all tumors exhibit the EPR effect (Jain, (1994) Barriers to Drug-Delivery in Solid Tumors. Scientific American 271, 58-65), and passively-targeted nanocarriers are no more effective at treating blood cancers than free drugs (Sapra & Allen (2002), Internalizing Antibodies are Necessary for Improved Therapeutic Efficacy of Antibody-Targeted Liposomal Drugs. Cancer Res 62, 7190-7194). Selective targeting strategies employ ligands (e.g. peptides, monoclonal antibodies, aptamers, vitamins, etc.) that specifically interact with receptors expressed on the cell surface of interest to promote nanocarrier binding and internalization (Torchilin (2005), Recent Advances with Liposomes as Pharmaceutical Carriers. Nat Rev Drug Discov 4, 145-160). This strategy requires that receptors are highly over-expressed by cancer cells (104-105 copies/cell) relative to normal cells in order to maximize selectivity and therapeutic efficacy. Additionally, multiple copies of a targeting ligand can be conjugated to the nanocarrier surface to promote multivalent binding effects, which result in enhanced affinity and more efficient drug delivery through the receptor-mediated internalization pathways that help circumvent MDR efflux mechanisms (Pastan, Hassan, FitzGerald, & Kreitman (2006), Immunotoxin Therapy of Cancer. Nat Rev Cancer 6, 559-565).
Liposomes are one of the extensively studied classes of nanocarriers due to their biocompatibility and biodegradability, as well as the ease with which they can be surface-modified with targeting ligands and polyethylene glycol (PEG) to control functionality and improve circulation times. Liposomes are the first drug carrying nanoparticles to reach the clinic, but today, more than two decades after the regulatory approval of liposomal doxorubicin (Doxil) to treat AIDS-related Kaposi's sarcoma and other cancers (Gordon, et al. (2001) Recurrent Epithelial Ovarian Carcinoma: a Randomized Phase III Study of Pegylated Liposomal Doxorubicin Versus Topotecan. J Clin Oncol 19, 3312-3322), no targeted liposomes have cleared Phase I clinical trials.
The major challenge for liposomes and other targeted nanocarriers is to simultaneously achieve high targeting specificity and delivery efficiency, while avoiding non-specific binding and entrapment by the body's defences. Other desirable characteristics include a high capacity for disparate types of therapeutic and diagnostic agents, the ability to controllably release encapsulated cargo upon internalization within the target cell, stability, solubility, and lack of immunogenicity. In some cases, it is also desirable to direct the intracellular targeting of delivered cargo in order to maximize therapeutic efficacy.
Applicants have overcome these and other problems and provide effective materials and methods for synthesizing targeted nanocarriers.